Interleukin-6 is a candidate molecule that transmits inflammatory information to the CNS

Oka, Yuichi; Ibuki, Takae; Matsumura, Kiyoshi; Namba, Mark D.; Yamazaki, Yasuo; Poole, S.; Tanaka, Yoshifumi; Kobayashi, Shígeo

doi:10.1016/j.neuroscience.2006.10.055

Cited by 57 publications

(56 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We showed that high levels of IL-6/CXCL6 protein boosted by inflammation are reduced with use of PRP. Neutralization of IL-6/ CXCL6 can attenuate hyperalgesia [31]. Whether lowering MCP-1/CCL2 and IL-6/CXCL6 levels by means of PRP is clinically relevant in this context needs further confirmation.…”

Section: Discussionmentioning

confidence: 98%

“…PRP could help in recovering homeostasis under pathological conditions because it downregulates inflammatory gene expression and immunomodulatory/angiogenic protein secretion in already inflamed tendon cells. Neutralization of proinflammatory cytokines can attenuate hyperalgesia [31], but whether the reduction induced by PRP is clinically important warrants further investigation. …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Platelet-rich Plasma Modulates the Secretion of Inflammatory/Angiogenic Proteins by Inflamed Tenocytes

Andı́a

Rubio‐Azpeitia

Maffulli

2015

Clinical Orthopaedics &Amp; Related Research

View full text Add to dashboard Cite

Background Platelet-rich plasma therapies for tendinopathy appear to provide moderate pain reduction. However, the biological mechanisms behind the observed clinical effects remain poorly characterized. Questions/purposes The purpose of this study was to explore whether platelet-rich plasma modifies the inflammatory/angiogenic status of already inflamed tenocytes by examining (1) gene expression; (2) modulation of chemokine and interleukin secretion; and (3) differences between healthy and tendinopathic tenocytes. Methods Cells from both healthy and tendinopathic tendons were exposed to interleukin (IL)-1ß and after treated with platelet-rich plasma. Modifications in the expression of selected genes were assessed by real-time reverse transcription-polymerase chain reaction and changes in secretion of angiogenic/inflammatory molecules by enzyme-linked immunosorbent assay. Platelet-rich plasmainduced changes in tendinopathic cells were compared with normal after normalizing platelet-rich plasma data against IL-1ß status in each specific sample. Results In IL-1ß-exposed cells, platelet-rich plasma downregulates expression of IL-6/CXCL-6 (mean, 0.015; 95% confidence interval [CI], 0.005-0.025; p = 0.026), IL-6R (mean, 0.61; 95% CI, 0.27-0.95; p = 0.029), and IL-8/CXCL-8 (mean, 0.02; 95% CI, 0.007-0.023; p = 0.026). Secretion of IL-6/CXCL6, 0.35 (95% CI, 0.3-0.4; p = 0.002), IL-8/CXCL8, 0.55 (95% CI, 0.5-0.7; p = 0.01), and monocyte chemoattractant protein-1/CCL2, 0.40 (95% CI, 0.2-0.6; p = 0.001) was reduced by platelet-rich plasma, whereas vascular endothelial growth factor increased by twofold, (95% CI, 1.7-2.3; p \ 0.001). RANTES/CCL5 increased by10-fold (95% CI, 4-17) and hepatocyte growth factor by 21-fold (95% CI, 0.2-42) in tendinopathic and by 2.3-fold (95% CI, 2-3) and threefold (95% CI, 1-5) in normal cells (p = 0.005 for both). Conclusions Platelet-rich plasma induces an immunomodulatory and proangiogenic phenotype consistent with healing mechanisms with few differences between tendinopathic and normal cells. Clinical Relevance Platelet-rich plasma injections in pathological and nearby tissue might help to recover tendon homeostasis.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Platelet-rich Plasma Modulates the Secretion of Inflammatory/Angiogenic Proteins by Inflamed Tenocytes

Andı́a

Rubio‐Azpeitia

Maffulli

2015

Clinical Orthopaedics &Amp; Related Research

View full text Add to dashboard Cite

show abstract

“…IL-1␤ is thought to activate IL-6, and circulating IL-6 concentrations are correlated with the upregulated expression of PG-synthesizing enzymes in the periphery and in brain vasculature (5,34,49). Humoral PGE 2 , produced by macrophages of the lungs and liver, was shown to initiate the first febrile phase in mammals (49), while subsequent febrile phases are thought to be mediated by an upregulated expression of PGE 2 in the brain itself as a result of the initiation of cyclooxygenase (COX)-2 and microsomal PGE synthase-1 in endothelial cells (34) and the cerebral microvasculature (39).…”

mentioning

confidence: 99%

Brain IL-6- and PG-dependent actions of IL-1β and lipopolysaccharide in avian fever

Marais

Maloney

Gray

2011

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Marais M, Maloney SK, Gray DA. Brain IL-6-and PG-dependent actions of IL-1␤ and lipopolysaccharide in avian fever. Am J Physiol Regul Integr Comp Physiol 301: R791-R800, 2011. First published June 15, 2011; doi:10.1152/ajpregu.00136.2011There is no persuasive evidence of a correlation between proinflammatory cytokines and avian fever. In this study, for the first time, we use avian cytokines to investigate a role for proinflammatory cytokines in the central component of avian fever. IL-1␤ and IL-6 injected intracerebroventricularly into Pekin ducks (n ϭ 8) initiated robust fevers of equal magnitude and duration, although there was a significant difference in the latency to a febrile response. In addition, the IL-1␤-induced fever could be abolished with an intracerebroventricular injection of antibodies to avian IL-6 or an oral administration of a PG synthesis inhibitor. Our findings indicate the following sequence of events within the central component of the avian febrile mechanism: IL-1␤ gives rise to bioactive IL-6, which stimulates an accelerated synthesis of PGs, and these PGs then adjust the sensitivity of warmsensitive neurons in the avian brain stem to mediate fever. Yet PGE 2 was not upregulated in the cerebrospinal fluid of ducks made febrile with LPS. We conclude that IL-1␤ and IL-6 may well mediate fever by instigating an accelerated synthesis of brain-derived PG, of a class other than PGE2, or that IL-6 serves as one of the terminal mediators of the avian febrile response.interleukin-1␤; interleukin-6; Pekin duck; prostaglandin E2 BIRDS, LIKE MAMMALS, DEVELOP fever when exposed to viruses and bacteria (25). The physiological mechanism responsible for febrile mediation in birds has not been elucidated. In homeothermic animals, thermoregulation is controlled by the central nervous system; therefore, fever, a nonthermal modifier of thermoregulation, requires adjustment of thermoregulatory controllers in the brain (35,46). The hypothalamus, with its temperature-sensitive neurons, serves as the dominant controller of temperature regulation in mammals, whereas the rostral brain stem is thought to house neurons that govern body temperature in birds (46). Despite these phylogenetic differences, it is clear that, in mammals and in birds, peripheral activation of the innate immune system results in physiological modifications at the site of thermoregulatory control.In mammals, proinflammatory cytokines, specifically IL-1␤ and IL-6, are known to act as mediators between the detection of an infectious stimulus by immune cells in the periphery and the stimulation of fever (5,(35)(36)(37). IL-1␤ is thought to activate IL-6, and circulating IL-6 concentrations are correlated with the upregulated expression of PG-synthesizing enzymes in the periphery and in brain vasculature (5,34,49). Humoral PGE 2 , produced by macrophages of the lungs and liver, was shown to initiate the first febrile phase in mammals (49), while subsequent febrile phases are thought to be mediated by an upregulated expression of PGE 2 in the br...

show abstract

“…While largely neglected at that time this study gained more attention when the antipyretic effect of local anesthetics blocking C-fiber-signaling was verified by Roth's group (Ross et al, 2000;Roth and De Souza, 2001). Several models for local inflammation have been used, including subcutaneous turpentine (Cooper and Rothwell, 1991;Fantuzzi et al, 1997;Horai et al, 1998;Kozak et al, 1998;Laflamme and Rivest, 1999;Leon et al, 1996), carrageenaninduced paw edema (Guay et al, 2004;Ibuki et al, 2003;Oka et al, 2007;Posadas et al, 2004;Prajapati et al, 2014), or immune stimuli administrated in artificial subcutaneous chambers (Cartmell et al, 2000;Miller et al, 1997;Rummel et al, 2005;Rummel et al, 2011;Zhang et al, 2008). However, most studies used local inflammation-models primarily to demonstrate an endotoxin-free cytokine-induced sickness syndrome (Horai et al, 1998;Kozak et al, 1998;Leon et al, 1996;Miller et al, 1997;Rivest et al, 2000) and not to investigate the role played by the afferent neurons.…”

Section: Afferent Neuronal Pathwaysmentioning

confidence: 99%

“…However, most studies used local inflammation-models primarily to demonstrate an endotoxin-free cytokine-induced sickness syndrome (Horai et al, 1998;Kozak et al, 1998;Leon et al, 1996;Miller et al, 1997;Rivest et al, 2000) and not to investigate the role played by the afferent neurons. Thus, a humoral component was present in these models for local inflammation with measurable circulating cytokines (Horai et al, 1998;Kozak et al, 1998;Miller et al, 1997;Oka et al, 2007;Rummel et al, 2011) and brain expression of IkBα (Laflamme and Rivest, 1999), COX-2 (Horai et al, 1998;Ibuki et al, 2003;Oka et al, 2007), and PGE2 (Guay et al, 2004;Ibuki et al, 2003;Oka et al, 2007).…”

Section: Afferent Neuronal Pathwaysmentioning

confidence: 99%

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

View full text Add to dashboard Cite

The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or nonhematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for proinflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

show abstract

Interleukin-6 is a candidate molecule that transmits inflammatory information to the CNS

Cited by 57 publications

References 41 publications

Platelet-rich Plasma Modulates the Secretion of Inflammatory/Angiogenic Proteins by Inflamed Tenocytes

Platelet-rich Plasma Modulates the Secretion of Inflammatory/Angiogenic Proteins by Inflamed Tenocytes

Brain IL-6- and PG-dependent actions of IL-1β and lipopolysaccharide in avian fever

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Contact Info

Product

Resources

About